DOCSLIB.ORG

The Hippo Pathway: Regulators and Regulations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Hippo Pathway: Regulators and Regulations Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The Hippo pathway: regulators and regulations Fa-Xing Yu and Kun-Liang Guan1 Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA Control of cell number is crucial in animal development a key node to coordinate these cellular processes (Fig. 1). and tissue homeostasis, and its dysregulation may result The Hippo pathway was first defined in Drosophila by in tumor formation or organ degeneration. The Hippo genetic mosaic screens for tumor suppressor genes. Ge- pathway in both Drosophila and mammals regulates cell netic inactivation of genes, including Warts (Wts) (Justice number by modulating cell proliferation, cell death, and et al. 1995; Xu et al. 1995), Hippo (Hpo) (Harvey et al. 2003; cell differentiation. Recently, numerous upstream com- Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; Wu ponents involved in the Hippo pathway have been iden- et al. 2003), Salvador (Sav;alsoknownasShar-Pei)(Kango- tified, such as cell polarity, mechanotransduction, and Singh et al. 2002; Tapon et al. 2002), and Mats (Lai et al. G-protein-coupled receptor (GPCR) signaling. Actin cyto- 2005), all resulted in a similar phenotype with robust skeleton or cellular tension appears to be the master tissue overgrowth. Yorkie (Yki) is the major downstream mediator that integrates and transmits upstream sig- effector of the Hippo pathway (Huang et al. 2005), which nals to the core Hippo signaling cascade. Here, we review regulates a transcription program by interacting with the regulatory mechanisms of the Hippo pathway and discuss transcription factor Scalloped (Sd) (Fig. 2; Goulev et al. potential implications involved in different physiological 2008; Wu et al. 2008; Zhang et al. 2008; Zhao et al. 2008). and pathological conditions. The Hippo pathway is highly conserved in mammals: MST1/2 (Hpo orthologs), Sav1, Lats1/2 (Wts orthologs), Cell proliferation, death, and differentiation are funda- and Mob1 (MOBKL1A and MOBKL1B, Mats orthologs) mental biological processes. Coordination of these pro- form a kinase cascade that phosphorylates and inhibits cesses is critical for a wide range of physiological and YAP/TAZ (Yki orthologs). YAP/TAZ in conjunction with pathological conditions (Pellettieri and Sanchez Alvarado TEAD1–4 (Sd orthologs) mediate major physiological 2007; Galliot and Ghila 2010). During development, an functions of the Hippo pathway (Fig. 2; for reviews, see increase in cell number is required to boost organ and Pan 2010; Zhao et al. 2010a). The nomenclature of many body size; meanwhile, proper differentiation of multiple components of the Hippo pathway in Drosophila and cell types will assure the appropriate function of devel- mammals is different, and a summary of these compo- oped organs. In adulthood, most tissues undergo contin- nents is shown in Table 1. uous cell turnover to maintain functionality. Aged or The core Hippo pathway has been well established in damaged cells are programmed to cell death, whereas both Drosophila and mammals; however, the regulatory adult stem cells may divide and differentiate to replace mechanisms for this signaling pathway are less under- those dysfunctional cells. Under pathological conditions, stood. Recently, by using both genetic and biochemical such as wound healing and organ regeneration, cell approaches, many additional components have been iden- division and differentiation of tissue-specific progenitor tified to modulate the core Hippo pathway (Table 1). In cells will be up-regulated to compensate for the lost cells. this review, we briefly describe the components of the On the other hand, uncontrolled cell proliferation and Hippo pathway and summarize recent advances with decreased cell death lead to hyperplasia or tumorigenesis. respect to Hippo pathway regulation. In addition, we also Detailed mechanisms underlying cell proliferation, cell discuss the implications of Hippo pathway regulation death, and cell differentiation have been extensively in different physiological and pathological conditions. studied; however, how these processes are coordinated The mammalian Hippo pathway is the main focus, al- and integrated is poorly understood. though some Drosophila works are also covered. For a Recently, the Hippo pathway has been shown to pro- detailed review on the Drosophila Hippo pathway, please mote cell death and differentiation and inhibit cell pro- refer to Staley and Irvine (2012). liferation; therefore, the Hippo pathway may function as Core Hippo pathway: a kinase cascade [Keywords: actin; GPCR; Hippo; YAP; mechanotransduction; polarity] MST1/2 are STE20 family protein kinases and can phos- 1Corresponding author E-mail [email protected] phorylate Sav1, Lats1/2, and Mob1 (Wu et al. 2003; Chan Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.210773.112. et al. 2005; Callus et al. 2006; Praskova et al. 2008). The GENES & DEVELOPMENT 27:355–371 Ó 2013 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/13; www.genesdev.org 355 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Yu and Guan 2007; Lei et al. 2008; Oh and Irvine 2008), in which the interaction may be mediated by PPxY motifs on Lats1/2 and WW domains on YAP/TAZ (Hao et al. 2008; Oka et al. 2008). Lats1/2 are AGC family kinases and recognize the substrate consensus sequence HXRXXS (Zhao et al. 2007). All five HXRXXS sites on YAP are directly phos- phorylated by Lats1/2 (Zhao et al. 2010b). The phosphor- ylated form of YAP is sequestered in the cytoplasm via a 14-3-3 interaction, resulting in inhibition of target gene transcription (Zhao et al. 2007). Also, TAZ and Yki are phosphorylated by Lats1/2 or Wts, respectively, on mul- tiple HXRXXS sites (Kanai et al. 2000; Dong et al. 2007; Lei et al. 2008; Oh and Irvine 2008; Ren et al. 2010b). In contrast, when upstream kinases are inactive, Yki/ YAP/TAZ will be hypophosphorylated and translocate into the nucleus to exert their functions on gene expres- Figure 1. Implications of the Hippo pathway in cell biology. sion (Kanai et al. 2000; Dong et al. 2007; Zhao et al. 2007; The Hippo pathway modulates cell proliferation, differentiation, Lei et al. 2008; Oh and Irvine 2008; Ren et al. 2010b). The growth, and death. The coordination of different cellular pro- phosphorylation status of YAP/TAZ also regulates their cesses by the Hippo pathway may contribute to diverse physio- protein stability. Phosphorylation of YAP (S381) and logical and pathological conditions such as development, tissue TAZ (S311) by Lats1/2 primes subsequent phosphoryla- homeostasis, and tumorigenesis. tion events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF kinase activity of MST1/2 is enhanced through interaction ubiquitin E3 ligase) and consequently leads to degradation with Sav1, which is mediated by SARAH (Sav/Rassf/Hpo) of YAP/TAZ (CY Liu et al. 2010; Zhao et al. 2010b). domains present in both MST1/2 and Sav1 (Callus et al. Therefore, by affecting YAP/TAZ protein localization 2006). In addition, the thousand-and-one (TAO) amino and stability, phosphorylation by upstream kinases rep- acids kinase or TAOK1–3 has been shown to directly resents a central regulatory mechanism for YAP/TAZ phosphorylate and activate Hpo or MST1/2 (Boggiano (Fig. 2). et al. 2011; Poon et al. 2011). In Drosophila, RASSF YAP/TAZ do not contain intrinsic DNA-binding do- competes with Sav for Hpo and recruits a PP2A com- mains but instead bind to the promoters of target genes plex (dSTRIPAK) to dephosphorylate and inactivate Hpo (Polesello et al. 2006; Ribeiro et al. 2010). However, mul- tiple RASSF isoforms in mammals showed different roles on the Hippo pathway (Praskova et al. 2004; Ikeda et al. 2009), suggesting a divergent role through evolution. MST1/2 directly phosphorylate Lats1/2 at the hydro- phobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation (Chan et al. 2005). Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity (Chan et al. 2005; Praskova et al. 2008). Sav1 may function as a bridge to bring MST1/2 and Lats1/2 together (Tapon et al. 2002; Callus et al. 2006) and may enhance or inhibit the activity of Lats1/2 upon phosphorylation by MST1/2 or salt-inducible kinases, respectively (Callus et al. 2006; Wehr et al. 2012). The requirement for MST1/2 to activate Lats1/2 might be cell type-dependent. For instance, MST1/2 knockout in mouse livers does not significantly affect Lats1/2 phosphoryla- tion (Zhou et al. 2009), suggesting that additional ki- Figure 2. The core Hippo pathway. MST1/2 phosphorylates Sav, Lats1/2, and Mob; Lats1/2 phosphorylates YAP/TAZ; and phos- nases may regulate Lats1/2 activity. In addition to protein phorylated YAP/TAZ interacts with 14-3-3 and results in cyto- phosphorylation, the protein levels of Lats1/2 kinases are plasmic retention. Moreover, YAP/TAZ phosphorylation leads controlled by Itch E3 ubiquitin ligase-mediated degrada- to protein degradation. When dephosphorylated, YAP/TAZ enter tion (Ho et al. 2011). nuclei and induce gene transcription by interacting with tran- Lats1/2 directly interact
Load more

Recommended publications
  • Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation
    BASIC RESEARCH www.jasn.org Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation † † Helen McNeill* and Antoine Reginensi *Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; and †Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada ABSTRACT In the kidney, formation of the functional filtration units, the nephrons, is essential for postnatal life. During development, mesenchymal progenitors tightly regulate the balance between self-renewal and differentia- tion to give rise to all nephron epithelia. Here, we investigated the functions of the Hippo pathway serine/ threonine-protein kinases Lats1 and Lats2, which phosphorylate and inhibit the transcriptional coactivators Yap and Taz, in nephron progenitor cells. Genetic deletion of Lats1 and Lats2 in nephron progenitors of mice led to disruption of nephrogenesis, with an accumulation of spindle-shaped cells in both cortical and medullary regions of the kidney. Lineage-tracing experiments revealed that the cells that accumulated in the interstitium derived from nephron progenitor cells and expressed E-cadherin as well as vimentin, a myofibroblastic marker not usually detected after mesenchymal-to-epithelial transition. The accumulation of these interstitial cells associated with collagen deposition and ectopic expression of the myofibroblastic markers vimentin and a-smooth-muscle actin in developing kidneys. Although these myofibroblastic cells had high Yap and Taz accumulation in the nucleus concomitant with a loss of phosphorylated Yap, reduction of Yap and/or Taz expression levels completely rescued the Lats1/2 phenotype. Taken together, our results demonstrate that Lats1/2 kinases restrict Yap/Taz activities to promote nephron progenitor cell differentiation in the mamma- lian kidney.
    [Show full text]
  • MAP4K Family Kinases Act in Parallel to MST1/2 to Activate LATS1/2 in the Hippo Pathway
    ARTICLE Received 19 Jun 2015 | Accepted 13 Aug 2015 | Published 5 Oct 2015 DOI: 10.1038/ncomms9357 OPEN MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway Zhipeng Meng1, Toshiro Moroishi1, Violaine Mottier-Pavie2, Steven W. Plouffe1, Carsten G. Hansen1, Audrey W. Hong1, Hyun Woo Park1, Jung-Soon Mo1, Wenqi Lu1, Shicong Lu1, Fabian Flores1, Fa-Xing Yu3, Georg Halder2 & Kun-Liang Guan1 The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members—Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7—as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway. 1 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
    [Show full text]
  • Machine-Learning and Chemicogenomics Approach Defi Nes and Predicts Cross-Talk of Hippo and MAPK Pathways
    Published OnlineFirst November 18, 2020; DOI: 10.1158/2159-8290.CD-20-0706 RESEARCH ARTICLE Machine -Learning and Chemicogenomics Approach Defi nes and Predicts Cross-Talk of Hippo and MAPK Pathways Trang H. Pham 1 , Thijs J. Hagenbeek 1 , Ho-June Lee 1 , Jason Li 2 , Christopher M. Rose 3 , Eva Lin 1 , Mamie Yu 1 , Scott E. Martin1 , Robert Piskol 2 , Jennifer A. Lacap 4 , Deepak Sampath 4 , Victoria C. Pham 3 , Zora Modrusan 5 , Jennie R. Lill3 , Christiaan Klijn 2 , Shiva Malek 1 , Matthew T. Chang 2 , and Anwesha Dey 1 ABSTRACT Hippo pathway dysregulation occurs in multiple cancers through genetic and non- genetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defi ning tumors that are Hippo pathway–dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type–agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage- independent signature for the Hippo pathway in cancers.
    [Show full text]
  • Ubiquitination‑Deubiquitination in the Hippo Signaling Pathway (Review)
    ONCOLOGY REPORTS 41: 1455-1475, 2019 Ubiquitination‑deubiquitination in the Hippo signaling pathway (Review) YANTING LIU and JUN DENG Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China Received April 3, 2018; Accepted September 17, 2018 DOI: 10.3892/or.2019.6956 Abstract. The Hippo signaling pathway is considered to be Ubiquitin modifications are involved in regulating various a tissue growth regulator and tumor suppressor pathway that physiological processes and are counteracted by deubiquiti- controls cell proliferation, differentiation, survival, regen- nation. Imbalanced ubiquitination-deubiquitination is closely eration and tissue homeostasis. Defects in Hippo kinases associated with tumor initiation and progression. Therefore, and hyperactivation of transcriptional co-activator with the examination of the specific association between the Hippo PDZ-binding motif and Yes-associated protein (YAP) may pathway and ubiquitination is of interest. The present study contribute to the development of different types of cancer. reviews the modulatory mechanism of ubiquitination-deubiq- The Hippo pathway is regulated in a variety of way, of which uitination in the Hippo signaling pathway, the recent progress ubiquitination is of considerable importance. Ubiquitination is in identifying therapeutic targets and strategies, and the future a crucial post‑translational protein modification in cancer cells directions in the field that may contribute to better tumor and is an applicable target for pharmacological intervention. diagnosis and treatment. Contents Correspondence to: Dr Jun Deng, Department of Oncology, The First Affiliated Hospital of Nanchang University, 17 Yong Wai 1. Introduction Zheng Street, Nanchang, Jiangxi 330006, P.R. China 2. Overview of the Hippo pathway E-mail: [email protected] 3.
    [Show full text]
  • Dysfunctional Mechanotransduction Through the YAP/TAZ/Hippo Pathway As a Feature of Chronic Disease
    cells Review Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease 1, 2, 2,3, 4 Mathias Cobbaut y, Simge Karagil y, Lucrezia Bruno y, Maria Del Carmen Diaz de la Loza , Francesca E Mackenzie 3, Michael Stolinski 2 and Ahmed Elbediwy 2,* 1 Protein Phosphorylation Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] 2 Department of Biomolecular Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] (S.K.); [email protected] (L.B.); [email protected] (M.S.) 3 Department of Chemical and Pharmaceutical Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] 4 Epithelial Biology Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] * Correspondence: [email protected] These authors contribute equally to this work. y Received: 30 November 2019; Accepted: 4 January 2020; Published: 8 January 2020 Abstract: In order to ascertain their external environment, cells and tissues have the capability to sense and process a variety of stresses, including stretching and compression forces. These mechanical forces, as experienced by cells and tissues, are then converted into biochemical signals within the cell, leading to a number of cellular mechanisms being activated, including proliferation, differentiation and migration. If the conversion of mechanical cues into biochemical signals is perturbed in any way, then this can be potentially implicated in chronic disease development and processes such as neurological disorders, cancer and obesity. This review will focus on how the interplay between mechanotransduction, cellular structure, metabolism and signalling cascades led by the Hippo-YAP/TAZ axis can lead to a number of chronic diseases and suggest how we can target various pathways in order to design therapeutic targets for these debilitating diseases and conditions.
    [Show full text]
  • Cell-Cell Interactions
    7 Cell-Cell Interactions Concept Outline 7.1 Cells signal one another with chemicals. Receptor Proteins and Signaling between Cells. Receptor proteins embedded in the plasma membrane change shape when they bind specific signal molecules, triggering a chain of events within the cell. Types of Cell Signaling. Cell signaling can occur between adjacent cells, although chemical signals called hormones act over long distances. 7.2 Proteins in the cell and on its surface receive signals from other cells. Intracellular Receptors. Some receptors are located within the cell cytoplasm. These receptors respond to lipid- soluble signals, such as steroid hormones. Cell Surface Receptors. Many cell-to-cell signals are water-soluble and cannot penetrate membranes. Instead, the signals are received by transmembrane proteins protruding out from the cell surface. 7.3 Follow the journey of information into the cell. FIGURE 7.1 Persimmon cells in close contact with one another. These Initiating the Intracellular Signal. Cell surface receptors plant cells and all cells, no matter what their function, interact often use “second messengers” to transmit a signal to the with their environment, including the cells around them. cytoplasm. Amplifying the Signal: Protein Kinase Cascades. Surface receptors and second messengers amplify signals as id you know that each of the 100 trillion cells of your they travel into the cell, often toward the cell nucleus. Dbody shares one key feature with the cells of tigers, bumblebees, and persimmons (figure 7.1)—a feature that 7.4 Cell surface proteins mediate cell-cell interactions. most bacteria and protists lack? Your cells touch and com- The Expression of Cell Identity.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Vocabulario De Morfoloxía, Anatomía E Citoloxía Veterinaria
    Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) Servizo de Normalización Lingüística Universidade de Santiago de Compostela COLECCIÓN VOCABULARIOS TEMÁTICOS N.º 4 SERVIZO DE NORMALIZACIÓN LINGÜÍSTICA Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) 2008 UNIVERSIDADE DE SANTIAGO DE COMPOSTELA VOCABULARIO de morfoloxía, anatomía e citoloxía veterinaria : (galego-español- inglés) / coordinador Xusto A. Rodríguez Río, Servizo de Normalización Lingüística ; autores Matilde Lombardero Fernández ... [et al.]. – Santiago de Compostela : Universidade de Santiago de Compostela, Servizo de Publicacións e Intercambio Científico, 2008. – 369 p. ; 21 cm. – (Vocabularios temáticos ; 4). - D.L. C 2458-2008. – ISBN 978-84-9887-018-3 1.Medicina �������������������������������������������������������������������������veterinaria-Diccionarios�������������������������������������������������. 2.Galego (Lingua)-Glosarios, vocabularios, etc. políglotas. I.Lombardero Fernández, Matilde. II.Rodríguez Rio, Xusto A. coord. III. Universidade de Santiago de Compostela. Servizo de Normalización Lingüística, coord. IV.Universidade de Santiago de Compostela. Servizo de Publicacións e Intercambio Científico, ed. V.Serie. 591.4(038)=699=60=20 Coordinador Xusto A. Rodríguez Río (Área de Terminoloxía. Servizo de Normalización Lingüística. Universidade de Santiago de Compostela) Autoras/res Matilde Lombardero Fernández (doutora en Veterinaria e profesora do Departamento de Anatomía e Produción Animal.
    [Show full text]
  • PI3K Catalytic Isoform Alteration Promotes the LIMK1-Related
    ANTICANCER RESEARCH 37 : 1805-1818 (2017) doi:10.21873/anticanres.11515 PI3K Catalytic Isoform Alteration Promotes the LIMK1-related Metastasis Through the PAK1 or ROCK1/2 Activation in Cigarette Smoke-exposed Ovarian Cancer Cells GA BIN PARK 1 and DAEJIN KIM 2 1Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea; 2Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea Abstract. Aim: To investigate the molecular mechanisms Several studies have shown a strong correlation between by which long-term exposure to cigarette smoke extract cigarette smoke (CS) and cancer metastasis through the (CSE) contributes to ovarian cancer metastasis. Materials induction of numerous factors involved in migration activity and Methods: Western blot analysis for diverse p110 (1-3). The exposure to CS induces the epithelial- isoforms of phosphoinositide 3-kinase (PI3K)-related mesenchymal transition (EMT) process and up-regulates the signaling pathway and epithelial-mesenchymal transition expression of EMT markers, including N-cadherin and (EMT) markers was performed to analyze the underlying vimentin (4, 5). Cigarette smoke extract (CSE) treatment mechanisms. Migratory activity of CSE-exposed ovarian significantly induces interleukin-8 (IL-8) and transforming cancer cells was determined by transendothelial migration growth factor-beta 1 (TGF- β1 ) production and profoundly and invasion assay. Results: After exposure to CSE for four suppresses the proliferation and growth of erythroid and weeks, CaOV3 (primary) and SKOV3 (metastatic) ovarian granulocyte-macrophage progenitors (6). Stimulation with cancer cells showed enhanced mesenchymal characteristics CSE in human lung fibroblast cells induces the expression and produced EMT-related cytokines [intwerleukin-8 (IL-8), of phosphorylated Smad3, a main downstream target of the vascular endothelial growth factor (VEGF) and TGF- β1 receptor, which results in the secretion of vascular transforming growth factor-beta 1 (TGF- β1 )].
    [Show full text]
  • Circular RNA Hsa Circ 0005114‑Mir‑142‑3P/Mir‑590‑5P‑ Adenomatous
    ONCOLOGY LETTERS 21: 58, 2021 Circular RNA hsa_circ_0005114‑miR‑142‑3p/miR‑590‑5p‑ adenomatous polyposis coli protein axis as a potential target for treatment of glioma BO WEI1*, LE WANG2* and JINGWEI ZHAO1 1Department of Neurosurgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033; 2Department of Ophthalmology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China Received September 12, 2019; Accepted October 22, 2020 DOI: 10.3892/ol.2020.12320 Abstract. Glioma is the most common type of brain tumor APC expression with a good overall survival rate. UALCAN and is associated with a high mortality rate. Despite recent analysis using TCGA data of glioblastoma multiforme and the advances in treatment options, the overall prognosis in patients GSE25632 and GSE103229 microarray datasets showed that with glioma remains poor. Studies have suggested that circular hsa‑miR‑142‑3p/hsa‑miR‑590‑5p was upregulated and APC (circ)RNAs serve important roles in the development and was downregulated. Thus, hsa‑miR‑142‑3p/hsa‑miR‑590‑5p‑ progression of glioma and may have potential as therapeutic APC‑related circ/ceRNA axes may be important in glioma, targets. However, the expression profiles of circRNAs and their and hsa_circ_0005114 interacted with both of these miRNAs. functions in glioma have rarely been studied. The present study Functional analysis showed that hsa_circ_0005114 was aimed to screen differentially expressed circRNAs (DECs) involved in insulin secretion, while APC was associated with between glioma and normal brain tissues using sequencing the Wnt signaling pathway. In conclusion, hsa_circ_0005114‑ data collected from the Gene Expression Omnibus database miR‑142‑3p/miR‑590‑5p‑APC ceRNA axes may be potential (GSE86202 and GSE92322 datasets) and explain their mecha‑ targets for the treatment of glioma.
    [Show full text]
  • The Legionella Kinase Legk7 Exploits the Hippo Pathway Scaffold Protein MOB1A for Allostery and Substrate Phosphorylation
    The Legionella kinase LegK7 exploits the Hippo pathway scaffold protein MOB1A for allostery and substrate phosphorylation Pei-Chung Leea,b,1, Ksenia Beyrakhovac,1, Caishuang Xuc, Michal T. Bonieckic, Mitchell H. Leea, Chisom J. Onub, Andrey M. Grishinc, Matthias P. Machnera,2, and Miroslaw Cyglerc,2 aDivision of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892; bDepartment of Biological Sciences, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202; and cDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N5E5, Canada Edited by Ralph R. Isberg, Tufts University School of Medicine, Boston, MA, and approved May 1, 2020 (received for review January 12, 2020) During infection, the bacterial pathogen Legionella pneumophila Active LATS1/2 phosphorylate the cotranscriptional regulator manipulates a variety of host cell signaling pathways, including YAP1 (yes-associated protein 1) and its homolog TAZ (tran- the Hippo pathway which controls cell proliferation and differen- scriptional coactivator with PDZ-binding motif). Phosphorylated tiation in eukaryotes. Our previous studies revealed that L. pneu- YAP1 and TAZ are prevented from entering the nucleus by being mophila encodes the effector kinase LegK7 which phosphorylates either sequestered in the cytosol through binding to 14-3-3 pro- MOB1A, a highly conserved scaffold protein of the Hippo path- teins or targeted for proteolytic degradation (6, 8). Consequently, way. Here, we show that MOB1A, in addition to being a substrate the main outcome of signal transduction along the Hippo pathway of LegK7, also functions as an allosteric activator of its kinase is changes in gene expression (6).
    [Show full text]
  • The Hippo Pathway Component Wwc2 Is a Key Regulator of Embryonic Development and Angiogenesis in Mice Anke Hermann1,Guangmingwu2, Pavel I
    Hermann et al. Cell Death and Disease (2021) 12:117 https://doi.org/10.1038/s41419-021-03409-0 Cell Death & Disease ARTICLE Open Access The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice Anke Hermann1,GuangmingWu2, Pavel I. Nedvetsky1,ViktoriaC.Brücher3, Charlotte Egbring3, Jakob Bonse1, Verena Höffken1, Dirk Oliver Wennmann1, Matthias Marks4,MichaelP.Krahn 1,HansSchöler5,PeterHeiduschka3, Hermann Pavenstädt1 and Joachim Kremerskothen1 Abstract The WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/ TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina.
    [Show full text]